Diagnostically relevant facial gestalt information from ordinary photos
Quentin Ferry, Julia Steinberg, Caleb Webber, David R FitzPatrick, Chris P Ponting, Andrew Zisserman, Christoffer Nellåker, Quentin Ferry, Julia Steinberg, Caleb Webber, David R FitzPatrick, Chris P Ponting, Andrew Zisserman, Christoffer Nellåker
Abstract
Craniofacial characteristics are highly informative for clinical geneticists when diagnosing genetic diseases. As a first step towards the high-throughput diagnosis of ultra-rare developmental diseases we introduce an automatic approach that implements recent developments in computer vision. This algorithm extracts phenotypic information from ordinary non-clinical photographs and, using machine learning, models human facial dysmorphisms in a multidimensional 'Clinical Face Phenotype Space'. The space locates patients in the context of known syndromes and thereby facilitates the generation of diagnostic hypotheses. Consequently, the approach will aid clinicians by greatly narrowing (by 27.6-fold) the search space of potential diagnoses for patients with suspected developmental disorders. Furthermore, this Clinical Face Phenotype Space allows the clustering of patients by phenotype even when no known syndrome diagnosis exists, thereby aiding disease identification. We demonstrate that this approach provides a novel method for inferring causative genetic variants from clinical sequencing data through functional genetic pathway comparisons.DOI: http://dx.doi.org/10.7554/eLife.02020.001.
Keywords: clinical genetics; computational biology; computer vision; phenotyping.
Conflict of interest statement
CPP: Senior editor, eLife.
The other authors declare that no competing interests exist.
Copyright © 2014, Ferry et al.
Figures
References
- Abecasis GR, Auton A, Brooks LD, Depristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, Mcvean GA. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65. doi: 10.1038/nature11632.
- Aldridge K, George ID, Cole KK, Austin JR, Takahashi TN, Duan Y, Miles JH. Facial phenotypes in subgroups of prepubertal boys with autism spectrum disorders are correlated with clinical phenotypes. Molecular Autism. 2011;2:15. doi: 10.1186/2040-2392-2-15.
- Allanson JE, Bohring A, Dorr HG, Dufke A, Gillessen-Kaesbach G, Horn D, Konig R, Kratz CP, Kutsche K, Pauli S, Raskin S, Rauch A, Turner A, Wieczorek D, Zenker M. The face of Noonan syndrome: does phenotype predict genotype. American Journal of Medical Genetics. 2010;152A:1960–1966. doi: 10.1002/ajmg.a.33518.
- Baird PA, Anderson TW, Newcombe HB, Lowry RB. Genetic disorders in children and young adults: a population study. American Journal of Human Genetics. 1988;42:677–693.
- Bastian M, Heymann S, Jacomy M. Gephi: An open source software for exploring and manipulating networks. AAAI Publications, Third International AAAI Conference on Weblogs and Social Media 2009
- Baynam G, Walters M, Claes P, Kung S, Lesouef P, Dawkins H, Gillett D, Goldblatt J. The facial evolution: looking backward and moving forward. Human Mutation. 2013;34:14–22. doi: 10.1002/humu.22219.
- Belhumeur PN, Jacobs DW, Kriegman DJ, Kumar N. Washington, DC, USA: IEEE Computer Society; 2011. Localizing parts of faces using a consensus of exemplars. Proceedings of the 2011 IEEE Conference on Computer Vision and Pattern Recognition; pp. 545–552.
- Bertola DR, Pereira AC, Brasil AS, Albano LM, Kim CA, Krieger JE. Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene. Journal of Human Genetics. 2007;52:521–526. doi: 10.1007/s10038-007-0146-1.
- Blanz V. Face recognition based on a 3D Morphable model. Proceedings Of the 7th International Conference of Automatic Face and Gesture Recognition. 2006:617–622.
- Boehringer S, Guenther M, Sinigerova S, Wurtz RP, Horsthemke B, Wieczorek D. Automated syndrome detection in a set of clinical facial photographs. American Journal of Medical Genetics. 2011;155A:2161–2169. doi: 10.1002/ajmg.a.34157.
- Boehringer S, Vollmar T, Tasse C, Wurtz RP, Gillessen-Kaesbach G, Horsthemke B, Wieczorek D. Syndrome identification based on 2D analysis software. European Journal of Human Genetics. 2006;14:1082–1089. doi: 10.1038/sj.ejhg.5201673.
- Bonferroni CE. Studi in Onore del Professore Salvatore Ortu Carboni. Rome, Italy: 1935. Il calcolo delle assicurazioni su gruppi di teste.
- Bonferroni CE. Teoria statistica delle classi e calcolo delle probabilità. Pubblicazioni del R Istituto Superiore di Scienze Economiche e Commerciali di Firenze. 1936:3–62.
- Bradski G. The OpenCV Library. Dr. Dobb's Journal of Software Tools 2000
- Buckley PF, Dean D, Bookstein FL, Han S, Yerukhimovich M, Min KJ, Singer B. A three-dimensional morphometric study of craniofacial shape in schizophrenia. The American Journal of Psychiatry. 2005;162:606–608. doi: 10.1176/appi.ajp.162.3.606.
- Cootes TF, Edwards GJ, Taylor CJ. Springer; 1998. Active appearance models. IEEE Transactions on Pattern Analysis and Machine Intelligence; pp. 484–498.
- Cordeddu V, Di Schiavi E, Pennacchio LA, Ma'ayan A, Sarkozy A, Fodale V, Cecchetti S, Cardinale A, Martin J, Schackwitz W, Lipzen A, Zampino G, Mazzanti L, Digilio MC, Martinelli S, Flex E, Lepri F, Bartholdi D, Kutsche K, Ferrero GB, Anichini C, Selicorni A, Rossi C, Tenconi R, Zenker M, Merlo D, Dallapiccola B, Iyengar R, Bazzicalupo P, Gelb BD., Tartaglia M. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nature Genetics. 2009;41:1022–1026. doi: 10.1038/ng.425.
- Dalal AB, Phadke SR. Morphometric analysis of face in dysmorphology. Computer Methods and Programs in Biomedicine. 2007;85:165–172. doi: 10.1016/j.cmpb.2006.10.005.
- de Ligt J, Willemsen MH, Van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-Van Silfhout AT, Koolen DA, De Vries P, Gilissen C, Del Rosario M, Hoischen A, Scheffer H, De Vries BB, Brunner HG, Veltman JA, Vissers LE. Diagnostic exome sequencing in persons with severe intellectual disability. The New England Journal of Medicine. 2012;367:1921–1929. doi: 10.1056/NEJMoa1206524.
- Dijkstra EW. A note on two problems in connexion with graphs. Numerische Mathematik. 1959;1:269–271. doi: 10.1007/BF01386390.
- Everingham M, Sivic J, Zisserman A. Taking the bite out of automatic naming of characters in TV video. Image and Vision Computing. 2009;27
- Ferrero GB, Biamino E, Sorasio L, Banaudi E, Peruzzi L, Forzano S, Di Cantogno LV, Silengo MC. Presenting phenotype and clinical evaluation in a cohort of 22 Williams-Beuren syndrome patients. European Journal of Medical Genetics. 2007;50:327–337. doi: 10.1016/j.ejmg.2007.05.005.
- Fischler MA, Elschlager RA. The representation and matching of pictorial structures. IEEE Transactions on Computer. 1973:67–92.
- Goodstadt L. Ruffus: a lightweight Python library for computational pipelines. Bioinformatics. 2010;26:2778–2779. doi: 10.1093/bioinformatics/btq524.
- Gordon AM. Abraham Lincoln–a medical appraisal. The Journal of the Kentucky Medical Association. 1962;60:249–253.
- Gripp KW, Lin AE, Nicholson L, Allen W, Cramer A, Jones KL, Kutz W, Peck D, Rebolledo MA, Wheeler PG, Wilson W, AL-Rahawan MM, Stabley DL, Sol-Church K. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. American Journal of Medical Genetics Part A. 2007;143A:1472–1480. doi: 10.1002/ajmg.a.31815.
- Hammond P. The use of 3D face shape modelling in dysmorphology. Archives of Disease in Childhood. 2007;92:1120–1126. doi: 10.1136/adc.2006.103507.
- Hammond P, Hutton TJ, Allanson JE, Buxton B, Campbell LE, Clayton-Smith J, Donnai D, Karmiloff-Smith A, Metcalfe K, Murphy KC, Patton M, Pober B, Prescott K, Scambler P, Shaw A, Smith AC, Stevens AF, Temple IK, Hennekam R, Tassabehji M. Discriminating power of localized three-dimensional facial morphology. American Journal of Human Genetics. 2005;77:999–1010.
- Hammond P, Suttie M. Large-scale objective phenotyping of 3D facial morphology. Human Mutation. 2012;33:817–825. doi: 10.1002/humu.22054.
- Hart TC, Hart PS. Genetic studies of craniofacial anomalies: clinical implications and applications. Orthodontics & Craniofacial Research. 2009;12:212–220. doi: 10.1111/j.1601-6343.2009.01455.x.
- Hennekam RC, Biesecker LG. Next-generation sequencing demands next-generation phenotyping. Human Mutation. 2012;33:884–886. doi: 10.1002/humu.22048.
- Hennessy RJ, Baldwin PA, Browne DJ, Kinsella A, Waddington JL. Three-dimensional laser surface imaging and geometric morphometrics resolve frontonasal dysmorphology in schizophrenia. Biological Psychiatry. 2007;61:1187–1194. doi: 10.1016/j.biopsych.2006.08.045.
- Hennessy RJ, Mclearie S, Kinsella A, Waddington JL. Facial shape and asymmetry by three-dimensional laser surface scanning covary with cognition in a sexually dimorphic manner. The Journal of Neuropsychiatry and Clinical Neurosciences. 2006;18:73–80. doi: 10.1176/appi.neuropsych.18.1.73.
- Hopper RA, Kapadia H, Morton T. Normalizing facial ratios in apert syndrome patients with Le Fort II midface distraction and simultaneous zygomatic repositioning. Plastic and Reconstructive Surgery. 2013;132:129–140. doi: 10.1097/PRS.0b013e318290fa8a.
- Kleefstra T, Wortmann SB, Rodenburg RJ, Bongers EM, Hadzsiev K, Noordam C, Van Den Heuvel LP, Nillesen WM, Hollody K, Gillessen-Kaesbach G, Lammens M, Smeitink JA, Van der Burgt I, Morava E. Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway. European Journal of Human Genetics. 2011;19:138–144. doi: 10.1038/ejhg.2010.171.
- Kratz CP, Zampino G, Kriek M, Kant SG, Leoni C, Pantaleoni F, Oudesluys-Murphy AM, Di Rocco C, Kloska SP, Tartaglia M, Zenker M. Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations. American Journal of Medical Genetics Part A. 2009;149A:1036–1040. doi: 10.1002/ajmg.a.32786.
- Kruskal WH, Wallis WA. Use of ranks in one-Criterion variance analysis. Journal of the American Statistical Association. 1952;47:583–621. doi: 10.1080/01621459.1952.10483441.
- Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, Cordeddu V, Williams BJ, Dentici ML, Caputo V, Venanzi S, Bonaguro M, Kavamura I, Faienza MF, Pilotta A, Stanzial F, Faravelli F, Gabrielli O, Marino B, Neri G, Silengo MC, Ferrero GB, Torrrente I, Selicorni A, Mazzanti L, Digilio MC, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Human Mutation. 2011;32:760–772. doi: 10.1002/humu.21492.
- Loos HS, Wieczorek D, Wurtz RP, Von Der Malsburg C, Horsthemke B. Computer-based recognition of dysmorphic faces. European Journal of Human Genetics. 2003;11:555–560. doi: 10.1038/sj.ejhg.5200997.
- Makita Y, Narumi Y, Yoshida M, Niihori T, Kure S, Fujieda K, Matsubara Y, Aoki Y. Leukemia in Cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene. Journal of Pediatric Hematology/oncology. 2007;29:287–290. doi: 10.1097/MPH.0b013e3180547136.
- Nystrom AM, Ekvall S, Berglund E, Bjorkqvist M, Braathen G, Duchen K, Enell H, Holmberg E, Holmlund U, Olsson-Engman M, Anneren G, Bondeson ML. Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. Journal of Medical Genetics. 2008;45:500–506. doi: 10.1136/jmg.2008.057653.
- Orphanet . Prevalence of rare diseases: Bibliographic data. In: KREMP O, editor. Orphanet Report Series. 2013.
- Oti M, Brunner HG. The modular nature of genetic diseases. Clinical Genetics. 2007;71:1–11. doi: 10.1111/j.1399-0004.2006.00708.x.
- Ramnath K, Koterba S, Xiao J, Hu C, Matthews I, Baker S, Cohn J, Kanade T. Multi-view AAM fitting and construction. International Journal of Computer Vision. 2008;76:183–204. doi: 10.1007/s11263-007-0050-3.
- Rauen KA. Cardiofaciocutaneous syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews. Seattle, WA: 1993.
- Rauen KA. Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. American Journal of Medical Genetics Part A. 2006;140:1681–1683. doi: 10.1002/ajmg.a.31315.
- Rauen KA. HRAS and the Costello syndrome. Clinical Genetics. 2007;71:101–108. doi: 10.1111/j.1399-0004.2007.00743.x.
- Rimoin DL, Hirschhorn K. A history of medical genetics in pediatrics. Pediatric Research. 2004;56:150–159. doi: 10.1203/01.PDR.0000129659.32875.84.
- Rossin EJ, Lage K, Raychaudhuri S, Xavier RJ, Tatar D, Benita Y, Cotsapas C, Daly MJ. Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLOS Genetics. 2011;7:e1001273. doi: 10.1371/journal.pgen.1001273.
- Schulz AL, Albrecht B, Arici C, Van der Burgt I, Buske A, Gillessen-Kaesbach G, Heller R, Horn D, Hubner CA, Korenke GC, Konig R, Kress W, Kruger G, Meinecke P, Mucke J, Plecko B, Rossier E, Schinzel A, Schulze A, Seemanova E, Seidel H, Spranger S, Tuysuz B, Uhrig S, Wieczorek D, Kutsche K, Zenker M. Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. Clinical Genetics. 2008;73:62–70. doi: 10.1111/j.1399-0004.2007.00931.x.
- Schuurs-Hoeijmakers JH, Oh EC, Vissers LE, Swinkels ME, Gilissen C, Willemsen MA, Holvoet M, Steehouwer M, Veltman JA, De Vries BB, Van Bokhoven H, De Brouwer AP, Katsanis N, Devriendt K, Brunner HG. Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. American Journal of Human Genetics. 2012;91:1122–1127. doi: 10.1016/j.ajhg.2012.10.013.
- Siegel DH, Mckenzie J, Frieden IJ, Rauen KA. Dermatological findings in 61 mutation-positive individuals with cardiofaciocutaneous syndrome. The British Journal of Dermatology. 2011;164:521–529. doi: 10.1111/j.1365-2133.2010.10122.x.
- Simonyan K, Parkhi OM, Vedaldi A, Zisserman A. Fisher Vector Faces in the Wild. British Machine Vision Conference 2013
- Sotos JG. Abraham Lincoln's marfanoid mother: the earliest known case of multiple endocrine neoplasia type 2B? Clinical Dysmorphology. 2012;21:131–136. doi: 10.1097/MCD.0b013e328353ae0c.
- Suttie M, Foroud T, Wetherill L, Jacobson JL, Molteno CD, Meintjes EM, Hoyme HE, Khaole N, Robinson LK, Riley EP, Jacobson SW, Hammond P. Facial dysmorphism across the fetal alcohol spectrum. Pediatrics. 2013;131:e779–e788. doi: 10.1542/peds.2012-1371.
- Tidyman WE, Rauen KA. Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway. Expert Reviews in Molecular Medicine. 2008;10:e37. doi: 10.1017/S1462399408000902.
- Twigg SR, Vorgia E, Mcgowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M, Zaragkoulias A, Sadighi Akha E, Knight SJ, Lord H, Lester T, Izatt L, Lampe AK, Mohammed SN, Stewart FJ, Verloes A, Wilson LC, Healy C, Sharpe PT, Hammond P, Hughes J, Taylor S, Johnson D, Wall SA, Mavrothalassitis G, Wilkie AO. Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis. Nature Genetics. 2013;45:308–313. doi: 10.1038/ng.2539.
- Viola P, Jones M. Rapid object detection using a boosted cascade of simple features. Computer Vision and Pattern Recognition, 2001. CVPR 2001. Proceedings of the 2001 IEEE Computer Society Conference on, 2001. 2001 I-511-I-518 vol. 1.
- Vollmar T, Maus B, Wurtz RP, Gillessen-Kaesbach G, Horsthemke B, Wieczorek D, Boehringer S. Impact of geometry and viewing angle on classification accuracy of 2D based analysis of dysmorphic faces. European Journal of Medical Genetics. 2008;51:44–53. doi: 10.1016/j.ejmg.2007.10.002.
- Weinberger KQ, Saul LK. Distance metric learning for large margin nearest neighbor classification. Journal of Machine Learning Research. 2009;10:207–244.
- Weischenfeldt J, Symmons O, Spitz F, Korbel JO. Phenotypic impact of genomic structural variation: insights from and for human disease. Nature Reviews Genetics. 2013;14:125–138. doi: 10.1038/nrg3373.
- Wright EM, Kerr B. RAS-MAPK pathway disorders: important causes of congenital heart disease, feeding difficulties, developmental delay and short stature. Archives of Disease in Childhood. 2010;95:724–730. doi: 10.1136/adc.2009.160069.
- Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA, De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA, Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri G, Tartaglia M. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Human Mutation. 2007;28:265–272. doi: 10.1002/humu.20431.
- Zenker M. Genetic and pathogenetic aspects of Noonan syndrome and related disorders. Hormone Research. 2009;72(suppl 2):57–63. doi: 10.1159/000243782.
Source: PubMed